The polychlorinated biphenyls (PCBs) are found universally as toxic environmental pollutants. The objectives of the proposed research program are to determine the mechanisms of hepatic microsomal metabolism of selected individual PCBs and to relate this metabolism to the toxicity of the corresponding PCB. The role of the number and position of chloride substituents on the PCBs in controlling metabolite patterns and toxicity will be determined and used to predict the toxicity of untested PCBs. The inductive effects of PCBs on hepatic microsomal mixed function oxidases and the consequences of such induction for hepatic drug and xenobiotic metabolism will also be investigated. Mechanisms of PCB metabolism will be investigated by (1) the determination of binding constants for PCB-hepatic cytochrome P-450 interactions in rat and monkey microsomes using difference spectral techniques; (2) isolation, using high pressure liquid chromatography, and identification, using mass spectrometry and NMR, of the metabolic products of the in vitro metabolism of selected PCBs by hepatic microsomes; (3) molecular orbital calculations of PCBs and theoretical reactive intermediate metabolites (e.g., arene oxides) using extended Huckel and CNDO/2 calculations; (4) the study of the covalent binding of C14 labeled PCB metabolites to microsomal macromolecules; and (5) the investigation of the effect of epoxide hydrase and glutathione S-epoxide transferase on the in vitro metabolism of PCBs by microsomal and solubilized rat enzyme systems. The acute and chronic inductive effects of PCBs will be probed in rats using quantitative assays of hepatic microsomal enzyme levels and determinations of drug metabolism activities. The results of these studies will be used to estimate safe levels of PCBs of differing chlorine contents. A number of the metabolic studies will be repeated using chlorinated dibenzofurans as substrates. These compounds frequently occur as impurities in PCBs and these studies should resolve the possibility of dibenzofurans being the source of toxic effects normally attributed to PCBs.